This invention relates to a process for selectively cleaving an amic acid function from a cephalosporin having an amic acid function in its 7-position, or from a penicillin having an amic acid function in its 6-position and to compounds useful as intermediates in this process.
It has been a customary practice for some time in the development of cephalosporin or penicillin antibiotics to employ an imide substituent in the 7- or 6-position when that portion of the molecule was not the point of investigation. The presence of such a protective group, particularly the phthalimido group, tended to render this position chemically quite inert and afforded the possibility to modify other portions of the molecule rather extensively with the relative assurance that this position would remain intact.
However, it has long been recognized that the presence of an imide function in the 7-position of a cephalosporin or the 6-position of a penicillin rendered the structure antibiotically only minimally active. Unfortunately, it has been impossible successfully to cleave an imido group from a cephalosporin or penicillin to liberate the protected amino group. Thus, the investigator was left with a stable substituent in this position which afforded a penicillin or cephalosporin exhibiting only minimal antibiotic activity. The use of such a substituent thus could be attractive commercially only if it could conveniently be removed at any desired point in a synthetic scheme.
It is not intended by the above to say, in general, that it has been impossible successfully to cleave an imide group. Several methods for accomplishing this are recognized. The Japanese publication by Minoru Shindo, "Cleavage Reactions of the Phthalimido Group", Yuki Gosei Kagaku Kyokai Shi, 29 (5), (1971) pp. 496-509, contains an extensive discussion of cleavage techniques. Any of these would be available in achieving cleavage of the imide function from a cephalosporin or penicillin were this the only essential consideration. However, it is at least of equal importance to employ conditions which will accomplish cleavage without sacrificing the structual integrity of the cephalosporin or penicillin molecule. To date, this has been impossible to achieve.
It has been possible to achieve a partial cleavage of the imide side chain of a cephalosporin- or penicillin-like structure to form the corresponding amic acid side chain (see, for example, Sheehan et al., Journal of the American Chemical Society, 73, (1951) pp. 4367-4372; Sheehan et al., Journal of the American Chemical Society, 78, (1956) pp. 3680-3683; Perron et al., Journal of Organic Chemistry, 7, (1964) pp. 483-487). The phthalimide function has been converted to the corresponding phthalamic acid by alkaline hydrolysis such as is described in the first Sheehan publication. However, as noted in the second Sheehan publication, all attempts to carry the cleavage beyond this point have met with failure, the .beta.-lactam ring of the penicillin being preferentially opened with destruction of the penicillin.
Sheehan, U.S. Pat. No. 3,487,074, discloses the cleavage of 6-phthalimido-3-penamyl-carboxylic acid by treatment thereof with hydrazine hydrate in dioxane for 12 hours at room temperature. However, this method has been found to be unsuccessful when applied to penicillins and cephalosporins, although moderate success was experienced when this approach was applied to a 7-phthalimido .DELTA..sup.2 -cephalosporin [see Spry, D. O., Journal of the American Chemical Society, 92, (1970), p. 5007].
A method has now been discovered by which an amic acid function of a cephalosporin or penicillin can be cleaved without opening the .beta.-lactam ring. This invention comprises such a method. Normally, the amic acid function will be obtained from partial cleavage of an imide function; however, this is by no means essential. Another aspect of this invention is directed to novel intermediates useful in achieving cleavage of the amic acid function as well as to separate conversion steps in the overall cleavage process.